CN106188045A - Compound, compositions and application thereof as WNT signal transduction inhibitor - Google Patents

Compound, compositions and application thereof as WNT signal transduction inhibitor Download PDF

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CN106188045A
CN106188045A CN201610534447.6A CN201610534447A CN106188045A CN 106188045 A CN106188045 A CN 106188045A CN 201610534447 A CN201610534447 A CN 201610534447A CN 106188045 A CN106188045 A CN 106188045A
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base
wnt
picoline
cancer
compound
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CN106188045B (en
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安松柱
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Curegenix Inc
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Abstract

The present invention relates to the compound of the structure with logical formula (I) of a kind of inhibitor as WNT signal transduction pathway and comprise the compositions of described compound.Furthermore, the present invention relates to the application in terms of suppression WNT signal transduction pathway of the described compound and the method for suppression WNT signal transduction pathway.

Description

Compound, compositions and application thereof as WNT signal transduction inhibitor
The application is that December in 2014 enters National Phase in China, Application No. 201280073873.4, the applying date on 10th Be on June 15th, 2012, invention entitled " as compound, compositions and the application thereof of WNT signal transduction inhibitor " send out The divisional application of bright patent application.
Technical field
The compound that the present invention relates to a kind of inhibitor as WNT signal transduction pathway and the group comprising this compound Compound.Furthermore, the present invention relates to the application in suppression WNT signal transduction pathway of the described compound and suppression WNT The method of signal transduction pathway.
Background technology
The conduction of WNT signal has vital effect to fetal development and the adult stable state of adult animal.WNT path is total It is made up of the protein network of regulation following three process on body: 1, the generation of WNT protein and secretion；2, WNT protein and cell The combination of receptor；3, intracellular transduction by interact trigger biochemical reaction (Mikels and Nusse, 2006； MacDonald,2009；Moon,2005).
The classics triggered by WNT protein and the combination of cell surface co-receptor FZ (Frizzled) LRP5/6 WNT path causes the amount arriving nuclear beta chain albumen to change, in nucleus, and beta chain albumen and TCF/LEF family Transcription factor interacts, thus promotes transcribing of specific gene.
By the non-classical WNT path of a series of different intracellular proteins conduction control insect bodies inner plane cell polarity with And the several process of formation gastrula etc in such as vertebrates body.
WNT signal known in the art conduction is sent out in terms of controlling embryonic stem cell and the versatility of adult stem cell and differentiation The effect of waving (Nusse, 2008).For example, during being formed gastrula, the formation of former bar and local WNT in embryoid Activation is relevant (ten Berge, 2008).From embryonic stem cell or iPS cell, derivative such as heart cell, pancreatic beta cell, many Polytype cell of bar amine neuron and hepatocyte etc all by WNT regulate and control to be affected (Yang, 2008；D’Amour, 2006；Inestrosa and Arenas, 2010；Sullivan,2010).WNT path is at such as bone formation and Subchondral drilling etc Skeletal tissue growth in play very important effect (Hoeppner, 2009；Chun,2008).WNT signal conduction also with The neuron regeneration of adult central nervous system is relevant (Lie, 2005).
The change of WNT pathway activity can cause numerous disease.Such as, the superactivation of classical WNT path may result in abnormal thin Intracellular growth (Reya and Clevers, 2005).It is worth noting most, the colorectal carcinoma of 90% is by adenomatous polyp (APC) disappearance of gene causes, and described adenomatous polyp (APC) is the inhibitive factor of WNT/ beta chain albumen path (Kinzler and Vogelstein, 1996).The extracellular suppression of the high expressed of WNT protein and generally suppression WNT protein function because of The disappearance of son can cause WNT-dependent tumors (Polakis, 2007).On the other hand, non-classical WNT path also shows one The evolution of a little cancers plays a role (Camilli and Weeraratna, 2010).Up-to-date achievement in research displays that WNT Signal conduction further relates to cancer stem cell (Takahashi-Yanaga and Kahn, 2010).
Evidence show that the signal transduction pathway that targeting Wnt-mediates is useful in the treatment to a variety of diseases (Barker and Clevers, 2006).Cause APC that classical Wnt path generation composition activates, beta chain albumen or axle albumen- The sudden change of 1 is the vital event in multiple human cancer, described human cancer include colorectal carcinoma, melanoma, Hepatocarcinoma, gastric cancer, ovarian cancer and other cancers (Polakis, 2007).Genetic method or chemical method is used to block multiple Wnt path in cancer has shown restriction abnormal cell growth (Herbst and Kolligs, 2007).Further, this is suppressed Bar path can directly affect following cell: described cell maintains growth of cancer cells and makes cancer cell metastasis, and described cell quilt Think that traditional chemotherapeutic agents is had toleration.
In addition to the activation of the Wnt path caused except the sudden change of gene outcome of receptor downstream, other mechanism cause Abnormal Wnt pathway activity also with many related to cancer.These cancers include but not limited to: lung (minicell and non-small cell) Cancer, breast carcinoma, carcinoma of prostate, carcinoid, bladder cancer, epithelial malignancy, esophageal carcinoma, ovarian cancer, cervical cancer, endometrium Cancer, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid carcinoma, fibroma durum, acute myeloblastic leukemia (AML), chronic myelocytic leukemia (CML).The existing multiple autocrine depending on rise in this area or the Wnt letter of paracrine The cancerous cell example of number conduction, and from the cell line of osteosarcoma, breast carcinoma, head and neck cancer and ovarian cancer shown by from The Wnt signal conduction of secretion or paracrine prevent above-mentioned cell line by apoptotic affecting (Kansara, 2009； Bafico, 2004；Akiri, 2009；DeAlmeida, 2007；Chan, 2007；Chen, 2009；And Rhee, 2002).
Further, abnormal Wnt path relates to Fibrotic generation, and described fibrosis includes but not limited to: pulmonary fibrosis (such as, idiopathic pulmonary fibrosis and the fibrosis of radiation induction), renal fibrosis and hepatic fibrosis (Morrisey, 2003； Hwang,2009；Cheng,2008).
The Other diseases relevant to abnormal WNT signal conduction includes but not limited to: Disease of bone and cartilage (such as, dredge by sclerotin Pine disease and osteoarthritis)；The obesity relevant to type-II diabetes；Neurodegenerative diseases (such as alzheimer's disease) (Hoeppner, 2009；Ouchi, 2010；Blom, 2010 and Boonen, 2009).The conduction of WNT signal additionally aids oneself of HSC I updates and maintains, and the dysfunction of WNT signal conduction can cause the various diseases (such as leukemia) that caused by HSC and many Plant other blood associated cancer (Reya, 2005).
Therefore, the method for regulation and control WNT-dependent cell reaction and the discovery of compound provide one for regulating with logical The approach of the physiological function that the abnormal activity on road is relevant and provide treatment side for the disease relevant to the abnormal activity of path Method.
Summary of the invention
In general, the present invention provides a kind of compound as WNT signal transduction inhibitor and pharmaceutical composition thereof, with And the application that described compound is in terms of suppression WNT signal transduction pathway.
Lexical or textual analysis
" WNT signal transduction pathway " used herein or " WNT path " refer to that the combination of WNT protein and cell receptor is led Cause the path that cell behavior changes.WNT path relates to multiple protein, including FZ, disheveled protein (Disheveled), axle Albumen (Axin), APC, GSK3 β, beta chain albumen, LEF/TCF transcription factor, and relevant to the synthesis of WNT protein and secretion Molecule.The example of the protein involved by the secretion of functional WNT includes but not limited to: wntless/evenness interrupted(Wls/Evi)、porcupine(Porcn)、Vps35p.Wls/Evi is a kind of to have seven transmembrane structure Albumen, it is concentrated mainly in Golgi body and is necessary to Wg (fruit bat), MOM-2 (nematicide) and Wnt3A secretion.Its bag Containing conserved structural motif, the 26S Proteasome Structure and Function of this motif is at present also in unknown state.Porcupine (Porcn) is Petiolus Trachycarpi The film of acyltransferase combines a member of O-acyltransferase (MBOAT) family.The fatty acid modifying of Wnt is non-for the function of Wnt The most important.Wnt carries out palmitoylation on one or two high conservative sites.Therefore, the inhibitor of Porcn can block All functional Wnt signals conduct.Vps35p is the subunit of the multiprotein complex being referred to as retromer complex, this egg White complex relates to the transport of intracellular protein.Vps35p is entered capsule at combination target protein as WNT to recruit Bubble aspect plays a role.
" WNT pathway inhibitor " or " WNT signal transduction inhibitor " is a kind of organic molecule, and molecular weight is typically about 800g/mol or less than about 800g/mol, the activity of its suppression WNT signal conduction.
The term method of WNT path " suppression " refers to suppress relevant with the generation of functional WNT protein or and WNT protein The method of the relevant known biochemical events of cell effect.As noted herein, according to this definition, You Ji little Molecule can suppress WNT to react.
" WNT protein " is that one is combined with FZ and LRP5/6 co-receptor to activate classical or non-classical WNT letter Number conduction albumen.The instantiation of WNT protein includes: WNT-1 (NM005430), WNT-2 (NM003391), WNT-2B/ WNT-13(NM004185)、WNT-3(NM030753)、WNT3a(NM033131)、WNT-4(NM030761)、WNT-5A (NM003392)、WNT-5B(NM032642)、WNT-6(NM006522)、WNT-7A(NM004625)、WNT-7B (NM058238)、WNT-8A(NM058244)、WNT-8B(NM003393)、WNT-9A/WNT-14(NM003395)、WNT-9B/ WNT-15(NM003396)、WNT-10A(NM025216)、WNT-10B(NM003394)、WNT-11(NM004626)、WNT-16 (NM016087)。
" WNT path disease " refers to produce disease or the morbid state of abnormal WNT signal conduction.On the one hand, abnormal WNT Signal conduction refers in suspecting the cell suffering from disease or tissue beyond the WNT signal conducting water in normal cell or tissue Flat WNT signal level of conduction.In a particular aspects, the disease of WNT mediation comprises cancer or fibrosis.
Term " cancer " refers to be characterized as pathological state in the human body of uncontrolled cell proliferation.Example includes but does not limits In: cancer, lymphoma, blastoma and leukemia.Cancer more specifically example includes but not limited to: lung (minicell and non-little carefully Born of the same parents) cancer, breast carcinoma, carcinoma of prostate, carcinoid, bladder cancer, gastric cancer, cancer of pancreas, liver (hepatocyte) cancer, hepatoblastoma, Colon and rectum Cancer, head and neck squamous cell cancer, esophageal carcinoma, ovarian cancer, cervical cancer, carcinoma of endometrium, mesothelioma, melanoma, sarcoma, Osteosarcoma, liposarcoma, thyroid carcinoma, fibroma durum, acute myeloblastic leukemia (AML) and chronic myelocytic leukemia (CML)。
Term " fibrosis " refers to be generally characterized as pathology in the human body of fibroblastic uncontrolled propagation and the hardening of tissue State.Particular instance includes but not limited to: pulmonary fibrosis (idiopathic pulmonary fibrosis and the fibrosis of radiation induction), kidney fibrous Change, hepatic fibrosis (including liver cirrhosis).
" suppressing ", " treatment " or " Therapeutic Method " refers to remission method, Therapeutic Method and prevention or prevention and controls, its In, the purpose of described remission method, Therapeutic Method and prevention or prevention and controls is to alleviate or prevent target pathology disease or shape Condition.In an example, after being administered WNT signal transduction inhibitor, cancer patient can show tumor size and reduce." control Treat " or " Therapeutic Method " including: (1) suppression suffer from or show the disease in the pathology of disease or the subject of symptom Sick；(2) alleviation suffers from or shows the disease in the pathology of disease or the subject of symptom；And/or (3) make to suffer from or table Reveal the pathology of disease or the patient of symptom or disease in the patient produces any measurable reduction.WNT path presses down Preparation can prevent growth of cancer cells to a certain extent and/or kill cancerous cell, and described WNT pathway inhibitor can be suppression Cell growth and/or Cytotoxic.
Term " therapeutically effective amount " refers to effectively " treat " WNT of the WNT path disease in patient or mammal body The amount of pathway inhibitor.In treatment of cancer, the medicine of therapeutically effective amount can reduce the quantity of cancerous cell, reduces tumor chi Very little, anticancer penetrates into peripheral organs, suppresses neoplasm metastasis, and suppression tumor growth is to a certain degree, and/or necessarily Alleviate in degree and the one in the symptom of related to cancer or more than one symptom.
" combine " with a kind of other therapeutic agents or more than one other therapeutic agents administration include Tong Bu (simultaneously) administration and with Any sequentially.As used herein term " drug regimen " refers to mixing or combined activity composition and the product that obtains Product, and " drug regimen " include fixed Combination and the non-fixed combinations of active component.Term " fixed Combination " refers to single The form of entity or the form of single dosage form active component (the such as compound of formula (1)) and associating medicament are administered simultaneously in Patient.Term " non-fixed combinations " refers to and combine active component (such as the compound of formula (1)) as separate entity Medicament synchronizes, delivers medicine to patient simultaneously or sequentially and limit without special time, and the most this administering mode can be in the patient The active component for the treatment of effect level is provided.The second administering mode is also applied to cocktail type treatment, such as, be administered three kinds Or more than three kinds of active component.
" chemotherapeutics " is chemical compound useful in treatment cancer.Example includes but not limited to: gemcitabine, Yi Li For health, amycin, 5-fluorouracil, cytosine arabinoside (" Ara-C "), cyclophosphamide (Cyclophosphamide), tespamin, Busulfan, cytotoxin (Cytoxin), paclitaxel, methotrexate, cisplatin, melphalan, vinblastine and carboplatin.
Detailed description of the invention
On the one hand, the present invention provides the change of a kind of structure with following logical formula (I) as WNT signal transduction inhibitor Compound or its physiologically acceptable salt:
Wherein,
X1、X2、X3、X4、X5、X6、X7And X8Independently be CR4Or N；
Y1For hydrogen or C (R4)3, each R4Identical or different；
Y2And Y3Independently be hydrogen, halogen or C (R3)3, each R3Identical or different；
R1And R2Independently selected from: hydrogen, halogen, C1-6Alkyl, quinolyl,C6-30Aryl, containing 1-2 Selected from the heteroatomic 3-6 unit Heterocyclylalkyl of N, O and S, and containing 1-4 the heteroatomic 5 or 6 yuan of heteroaryls selected from N, O and S Base；Wherein, quinolyl,C6-30Each in aryl, 3-6 unit Heterocyclylalkyl and 5 or 6 yuan of heteroaryls can By 1 or 2 identical or different R4Optionally replace；
R3Separately it is selected from: hydrogen, halogen, cyano group, C1-6Alkyl and C1-6Alkoxyl, wherein, C1-6Alkyl and C1-6Alkane Each in epoxide can be by halogen, amino, hydroxyl, C1-6Alkoxyl or cyano group optionally replace；
R4Separately it is selected from: hydrogen, halogen, cyano group, C1-6Alkoxyl ,-S (O)2R5、-C(O)OR5、-C(O)R5、-C(O) NR6R7、C1-6Alkyl, C2-6Thiazolinyl and C2-6Alkynyl, wherein, C1-6Alkoxyl ,-S (O)2R5、-C(O)OR5、-C(O)R5、-C(O) NR6R7、C1-6Alkyl, C2-6Thiazolinyl and C2-6Each in alkynyl can be by halogen, amino, hydroxyl, C1-6Alkoxyl or cyano group are optional Ground replaces；
R5、R6And R7Independently selected from: hydrogen, C1-6Alkyl, C2-6Thiazolinyl and C2-6Alkynyl, wherein, C1-6Alkyl, C2-6Thiazolinyl and C2-6Each in alkynyl can be by halogen, amino, hydroxyl, C1-6Alkoxyl or cyano group optionally replace.
Specifically, logical formula (I) has following core texture, but is not limited to this:
In logical formula (I), X1、X2、X3And X4Defined ring can be any one in following groups, but is not limited to This:
Preferably, the R in formula I1And R2Can be independently selected from: hydrogen, fluorine, chlorine, methyl,Phenyl, morpholinyl, Piperazinyl and 5 or 6 yuan of heteroaryls, described 5 or 6 yuan of heteroaryls are selected from following groups:
Preferably, R4Can be identical or different, and be separately selected from: hydrogen, fluorine, chlorine, cyano group ,-CH3、-CHF2、- CF3、-OCH3、-COOCH3。
In one embodiment, at least one atom in formula I is to be selected from2H、3H、11C、13C、14C、15N、17O、18O 、35S、18F、36Cl and123At least one in corresponding isotope in I.
As used herein, such as, any substituent group (such as, CH2H atom in) includes that all suitable isotopes become Change form, such as H,2H and3H。
As it is used herein, such as, other atoms in any substituent group include that all suitable isotopes convert shape Formula, includes but not limited to:11C、13C、14C、15N、17O、18O、35S、18F、36Cl and/or123I。
In a preferred embodiment, the example of the compound of the present invention includes but not limited to following compounds or its physiology Acceptable salt on:
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
N-((5-(2-picoline-4-base) pyridine-2-base) methyl)-7-phenylquinazoline-4-amine；
N-(4-morpholinyl benzyl)-7-phenylquinazoline-4-amine；
N-((6-morpholinyl pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
N-((6-(2-methyl morpholine base) pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
N-((6-(4-methylpiperazine-1-yl)-pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
4-(5-(((7-phenylquinazoline-4-base) amino) methyl) pyridine-2-base) thiomorpholine 1,1-dioxide；
N-((6-(6-picoline-3-base) pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
N-((6-(5-picoline-3-base) pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
7-phenyl-N-((6-(pyridin-4-yl) pyridin-3-yl) methyl) quinazoline-4-amine；
7-phenyl-N-((6-(pyridin-3-yl) pyridin-3-yl) methyl) quinazoline-4-amine；
7-phenyl-N-((6-(pyridine-2-base) pyridin-3-yl) methyl) quinazoline-4-amine；
7-phenyl-N-((6-(pyridazine-4-base) pyridin-3-yl) methyl) quinazoline-4-amine；
7-phenyl-N-((6-(pyrazine-2-base) pyridin-3-yl) methyl) quinazoline-4-amine；
7-phenyl-N-((6-(pyrimidine-5-base) pyridin-3-yl) methyl) quinazoline-4-amine；
N-((6-(2-fluorinated pyridine-4-base) pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
N-((6-(4-methyl-1 H-imidazole-1-group) pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
N-((6-(1-methyl isophthalic acid H-pyrazoles-4-base) pyridin-3-yl) methyl)-7-phenylquinazoline-4-amine；
N-((5-(6-picoline-3-base) pyridine-2-base) methyl)-7-phenylquinazoline-4-amine；
N-(4-(2-picoline-4-base) benzyl)-7-phenylquinazoline-4-amine；
N-(4-(2-fluorinated pyridine-4-base) benzyl)-7-phenylquinazoline-4-amine；
N-benzyl-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-methylbenzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-mehtoxybenzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-fluorobenzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-chlorphenylmethyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-bromobenzene methyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-(trifluoromethy) benzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
4-((7-(2-picoline-4-base) quinazoline-4-base amino) methyl) benzonitrile；
N-(4-morpholinyl benzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-phenylphenylmethyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(3-fluoro-4-phenylphenylmethyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-(3-difluorophenyl) benzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
7-(3-difluorophenyl)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4-amine；
7-(3-chlorophenyl)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-m-tolyl quinazoline-4-amine；
3-(4-((6-(2-picoline-4-base) pyridin-3-yl) methylamino) quinazoline-7-base) benzonitrile；
4-(4-((6-(2-picoline-4-base) pyridin-3-yl) methylamino) quinazoline-7-base) benzonitrile；
7-(2-picoline-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4- Amine；
7-(6-picoline-3-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4- Amine；
7-(5-picoline-3-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4- Amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(pyridine-2-base) quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(pyridin-3-yl) quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(pyridin-4-yl) quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(pyridazine-4-base) quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(pyrazine-2-base) quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(pyrimidine-5-base) quinazoline-4-amine；
7-(2-fluorinated pyridine-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4- Amine；
7-(2-(trifluoromethy) pyridin-4-yl)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinoline Oxazoline-4-amine；
7-(2-methoxypyridine-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4- Amine；
7-(3-picoline-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4- Amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-morpholinyl quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(piperidin-1-yl) quinazoline-4-amine；
7-(4-methylpiperazine-1-yl)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4- Amine；
1-(4-(4-((6-(2-picoline-4-base) pyridin-3-yl) methylamino) quinazoline-7-base) piperazine-1- Base) ethyl ketone；
4-(4-(((2 '-methyl-[2,4 '-bipyridyl]-5-base) methyl) amino) quinazoline-7-base) thiomorpholine 1,1- Dioxide；
7-(1,2,3,6-tetrahydropyridine-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinoline azoles Quinoline-4-amine；
7-(1,2,3,6-tetrahydropyridine-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinoline azoles Quinoline-4-amine；
1-(4-(4-((6-(2-picoline-4-base) pyridin-3-yl) methylamino) quinazoline-7-base) piperidines-1- Base) ethyl ketone；
N-((2 '-methyl-[2,4 '-bipyridyl]-5-base) methyl)-7-(4-(methyl sulphonyl) piperazine-1-base) quinoline azoles Quinoline-4-amine；
7-(1-methyl isophthalic acid H-pyrazoles-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline- 4-amine；
7-(isoxazole-4-base)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) quinazoline-4-amine；
N-((6-(2-picoline-4-base) pyridin-3-yl) methyl)-7-(thiazol-2-yl) quinazoline-4-amine；
N-(3-methyl-4-(2-picoline-4-base) benzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(3-fluoro-4-(2-picoline-4-base) benzyl)-7-(2-picoline-4-base) quinazoline-4-amine；
N-(4-(2-picoline-4-base) benzyl)-7-(pyrazine-2-base) quinazoline-4-amine；
N-(4-(2-picoline-4-base) benzyl)-7-(2-fluorinated pyridine-4-base) quinazoline-4-amine；
N-(4-(2-picoline-4-base) benzyl)-7-morpholinyl quinazoline-4-amine；
2-(3-difluorophenyl)-N-(4-(2-picoline-4-base) benzyl) pyrido [3,4-b] pyrazine-5-amine；
2-(3-difluorophenyl)-N-((2 '-methyl-[2,4 '-bipyridyl]-5-base) methyl) pyrido [3,4-b] pyrazine- 5-amine；
2-(3-difluorophenyl)-N-(3-methyl-4-(2-picoline-4-base) benzyl) pyrido [3,4-b] pyrazine- 5-amine；
N-(3-fluoro-4-(2-picoline-4-base) benzyl)-2-(3-difluorophenyl) pyrido [3,4-b] pyrazine- 5-amine；
2-(2-picoline-4-base)-N-(4-(2-picoline-4-base) benzyl) pyrido [3,4-b] pyrazine-5- Amine；
N-((2 '-methyl-[2,4 '-bipyridyl]-5-base) methyl)-2-(2-picoline-4-base) pyrido [3,4-b] Pyrazine-5-amine；
N-(3-methyl-4-(2-picoline-4-base) benzyl)-2-(2-picoline-4-base) pyrido [3,4-b] Pyrazine-5-amine；
N-(3-fluoro-4-(2-picoline-4-base) benzyl)-2-(2-picoline-4-base) pyrido [3,4-b] Pyrazine-5-amine；
N-((2 ', 3-dimethyl-[2,4 '-bipyridyl]-5-base) methyl)-6-(pyrazine-2-base)-copyrine 2,7-1-amine；
6-(2-methyl morpholine base)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7-1-amine；
(S)-6-(2-methyl morpholine base)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7-1-amine；
(R)-6-(2-methyl morpholine base)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7-1-amine；
1-(4-(8-((4-(2-picoline-4-base) benzyl) amino)-copyrine 2,7-3-base) piperazine-1-base) second Ketone；
6-(1H-imidazoles-1-base)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7-1-amine；
6-(4-methyl-1 H-imidazole-1-group)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7-1-amine；
N-(4-(2-picoline-4-base) benzyl)-6-(1H-TETRAZOLE-5-base)-copyrine 2,7-1-amine；
6-(5-Methyl-1,3,4-oxadiazole-2-2-base)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7- 1-amine；
6-(1-methyl isophthalic acid H-pyrazole-3-yl)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7-1-amine；
N-(4-(2-picoline-4-base) benzyl)-6-(thiazole-5-base)-copyrine 2,7-1-amine；
N-(4-(2-picoline-4-base) benzyl)-6-(oxazole-5-base)-copyrine 2,7-1-amine；
N-((2 ', 3-dimethyl-[2,4 '-bipyridyl]-5-base) methyl)-6-(5-picoline-3-base)-2,7-naphthalene Pyridine-1-amine；
N-((2 ', 3-dimethyl-[2,4 '-bipyridyl]-5-base) methyl)-6-(2-picoline-4-base)-2,7-naphthalene Pyridine-1-amine；
N-((3-fluoro-2 '-methyl-[2,4 '-bipyridyl]-5-base) methyl)-6-(2-picoline-4-base)-2,7- Naphthyridines-1-amine；
N-((2 ', 3-dimethyl-[2,4 '-bipyridyl]-5-base) methyl)-6-(5-fluorinated pyridine-3-base)-2,7-naphthalene Pyridine-1-amine；
N-(3-methyl-4-(2-picoline-4-base) benzyl)-6-(pyrazine-2-base)-copyrine 2,7-1-amine；
N-(3-fluoro-4-(2-picoline-4-base) benzyl)-6-(pyrazine-2-base)-copyrine 2,7-1-amine；
4-(8-((4-(2-picoline-4-base) benzyl) amino)-copyrine 2,7-3-base) piperazine-1-carboxylate methyl ester；
4-(8-((4-(2-picoline-4-base) benzyl) amino)-copyrine 2,7-3-base) piperazine-2-ketone；
2-(4-(8-((4-(2-picoline-4-base) benzyl) amino)-copyrine 2,7-3-base) piperazine-1-base) second Nitrile；
2-methyl-4-(4-(((6-(2-picoline-4-base)-copyrine 2,7-1-base) amino) methyl) phenyl) pyridine- 1-oxide；
6-(2-chloro-pyridine-4-base)-N-((2 ', 3-dimethyl-[2,4 '-bipyridyl]-5-base) methyl)-2,7-naphthalene Pyridine-1-amine；
6-(2-chloro-pyridine-4-base)-N-(4-(2-picoline-4-base) benzyl)-copyrine 2,7-1-amine；
2 '-methyl-4-(((6-(2-picoline-4-base)-copyrine 2,7-1-base) amino) methyl)-2H-[1,4 '-connection Pyridine]-2-ketone；
2-(2-picoline-4-base)-5-(((6-(2-picoline-4-base)-copyrine 2,7-1-base) amino) methyl) Benzonitrile；
N-(3-methoxyl group-4-(2-picoline-4-base) benzyl)-6-(2-picoline-4-base)-copyrine 2,7- 1-amine；
N-((3-chloro-2 '-methyl-[2,4 '-bipyridyl]-5-base) methyl)-6-(2-picoline-4-base)-2,7- Naphthyridines-1-amine；
N-(4-(2-(difluoromethyl) pyridin-4-yl) benzyl)-6-(2-picoline-4-base)-copyrine 2,7-1- Amine.
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compound of the present invention also And described pharmaceutical composition generally includes at least one pharmaceutically acceptable carrier or diluent, wherein, described compound is Free form or the form of pharmaceutically acceptable salt.Such compositions can be Orally administered composition, Injectable composition or Suppository.Further, described compositions can be in a usual manner by mixing, pelletize or method for coating manufacture.
In embodiments of the present invention, described compositions is Orally administered composition, and it can be tablet or gelatine capsule.Excellent Selection of land, described Orally administered composition contains compound and a) diluent of the present invention, such as, lactose, glucose, sucrose, manna Alcohol, sorbitol, cellulose and/or glycine；B) lubricant, such as, silicon dioxide, Talcum, stearic acid, stearic magnesium salt or Calcium salt and/or Polyethylene Glycol；For tablet, described Orally administered composition includes c) binding agent, such as, magnesium silicate aluminium salt, shallow lake Powder paste, gelatin, tragamayth, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone；And when needing, D) disintegrating agent, such as, starch, agar, alginic acid or its sodium salt, or effervescent mixture can also be included；And/or e) additive, Such as, absorbent, coloring agent, flavoring agent and sweetener.
In another embodiment of the present invention, described compositions is Injectable composition, and it can be the vadose solutions such as aqueous Liquid or suspension.
In a further embodiment of the present invention, described compositions is suppository, can be by fats emulsion or suspension preparation Become.
Preferably, described compositions is aseptic and/or comprises adjuvant.Described adjuvant can be preservative, stabilizer, profit Humectant or emulsifying agent, solution promoters, for regulating the salt of osmotic pressure, buffer agent and/or their combination in any.
Alternatively, or in addition, described compositions can also comprise the upper valuable material of other treatment for different In application, such as, solubilizing agent, stabilizer, absorption enhancer, buffer agent and/or preservative.
In embodiments of the present invention, described compositions can apply to the preparation of applied dermally.This preparation bag Include compound and the carrier of the present invention of effective dose.Preferably, described carrier can include helping inhaling by Host Skin The pharmaceutically acceptable solvent received.The transcutaneous device comprising described preparation can also be used.Described transcutaneous device can be to stretch tight Band forms, described form of bandage comprises support member, bank containing described compound, optionally exists with controlled and predetermined speed In one period of longer time period, described compound is delivered to the rate controlling barrier of Host Skin and described equipment is fixed to skin The instrument of skin, described bank optionally comprises carrier.Further, it is also possible to use skeleton percutaneous preparation.
In another embodiment of the present invention, described compositions can be adapted for local application and (such as, is applied to skin And eyes) preparation, and, described compositions can be aqueous solution well-known in the art, ointment, cream or solidifying Glue.
On the other hand, the present invention provides a kind of by making the above-claimed cpd of cell with effective amounts or its physiologically may be used The method that the salt accepted or aforementioned pharmaceutical compositions suppression WNT secrete from cell.
Another further aspect, the present invention provide a kind of above-claimed cpd by effective dose or its physiologically acceptable salt or The method of WNT signal conduction in person's aforementioned pharmaceutical compositions suppression cell.In one embodiment, described cell is included in the food in one's mouth In breast animal body, and the amount being administered is therapeutically effective amount.In another embodiment, the suppression of WNT signal conduction can enter one Step causes the suppression that cell grows.In further embodiment, described cell is cancerous cell.In yet, Described cell is brotic cells.
The detection of cell proliferation uses in method well known to those skilled in the art.Such as, detect cell proliferation one Method is CellTiter-Glo easilyTMDetection, is provided by Promega (Madison, WI) Company.The step of this detection Including: willReagent joins in the cell that porous plate is cultivated.By sending out that photometer or imaging device are measured Optical signal is proportional to the ATP quantity of existence, and the ATP quantity existed is the most proportional to the living cells quantity in culture. Detect it addition, cell proliferation it be also possible to use colony-forming test known in the art.
The present invention also provides for the cancer that the compounds for treating of the present invention of a kind of effective dose is relevant to WNT signal transduction pathway Disease or the method for fibrosis.Those skilled in the art can be easy to by using the one in multiple technologies known in the art to divide Analysis cancerous cell determines that cancer is the most relevant to Wnt path.Such as, those skilled in the art can use immunity and detection of nucleic acids The albumen relevant to the conduction of Wnt signal or the exception of mRNA level in-site in method detection cancerous cell.
The cancer relevant to Wnt path or fibrosis include: wherein in Wnt signal transduction pathway one or more than one Cancer that the activity of individual component is raised relative to basic horizontal or fibrosis.In one embodiment, suppression Wnt path Can include suppressing Wnt secretion.In another embodiment, suppression Wnt path can include the downstream group suppressing cell surface receptor Point.In another embodiment, suppression Wnt secretion can include suppressing the work of any albumen involved by the secretion of functional WNT Property.
And, the invention provides and treat patient by the WNT inhibitor of therapeutically effective amount is delivered medicine to patient The method of WNT path disease.In one embodiment, described disease is (the most alive with the abnormal activity of WNT signal conduction Property improve) relevant cell proliferation disorders.In another embodiment, described disease is to be caused by the amount increase of WNT protein 's.In yet, cell proliferation disorders is cancer, includes but not limited to: lung (minicell and non-small cell) cancer, Breast carcinoma, carcinoma of prostate, carcinoid, bladder cancer, gastric cancer, cancer of pancreas, liver (hepatocyte) cancer, hepatoblastoma, colorectal cancer, head and neck Squamous cell cancer, esophageal carcinoma, ovarian cancer, cervical cancer, carcinoma of endometrium, mesothelioma, melanoma, sarcoma, osteosarcoma, Liposarcoma, thyroid carcinoma, fibroma durum, acute myeloblastic leukemia (AML) and chronic myelocytic leukemia (CML).Separately In one embodiment, cell proliferation disorders is fibrosis, includes but not limited to: pulmonary fibrosis (such as, idiopathic pulmonary fibrosis With radioactive fibrosis), renal fibrosis and hepatic fibrosis (including liver cirrhosis).In yet, described disease Disease is osteoarthritis, parkinson disease, retinopathy, degeneration of macula.
For therapeutic use, the compound of the present invention can by any acceptable method well known in the art with Therapeutically effective amount is individually dosed.In this article, therapeutically effective amount can according to the order of severity of disease, patient age with relative Health status, the drug effect of the compound used and other factors and there is the biggest change.Generally, it is about in daily dosage The result that 0.03mg/kg patient's body weight is obtained to Formulations for systemic administration under conditions of 2.5mg/kg patient's body weight it is to be shown as Satisfied result.In one embodiment, the daily dosage needed for the bigger mammal of the such as mankind be about 0.5mg extremely About 100mg.Preferably, described compound is administered with the separate doses reaching more than a day 4 times or is administered with sustained release forms.Real at another Executing in mode, the suitable unit dosage forms for oral administration includes about 1mg to 100mg active component.
Alternatively, the compound of the present invention can be as active component with therapeutically effective amount and a kind of or more than one treatment Agent administering drug combinations, such as drug regimen.Can produce when the compound of the present invention uses with chemotherapeutic agent known in the art Cooperative effect.Certain drug that the dosage of the compound of administering drug combinations according to the type of the combination medicine used, can be used, Treated disease etc. and different.
The compound of the present invention or a combination thereof thing can be by the administrations of any conventional.In one embodiment, The compound of the present invention or a combination thereof thing enteral administration, such as oral administration, and be administered in the form of a tablet or capsule.Separately In a kind of embodiment, the compound of the present invention or a combination thereof thing parenteral, and with injectable solution or suspension Form be administered.In another embodiment, the compound of the present invention or a combination thereof thing topical and with emulsion, solidifying The form of glue, ointment or cream is administered, or is administered with nose form or suppository form.
On the other hand, present invention also offers drug regimen, preferred reagent box, it includes a) the first medicament, described first Medicament is the pharmaceutically acceptable salt of the compound of the compound of the present invention of free form disclosed herein or the present invention Form, and b) at least one associating medicament.Additionally, described test kit can include its description being administered.
The combination of the present invention can external use or internal use.Preferably, preferable drug treatment effect can be by making Cell, tissue or organism contact single compositions or comprise the compound of the present invention and a kind of or medicine of more than one medicament Thing preparation realizes, or by making cells contacting two kinds or realizing more than two kinds of different compositionss or preparation, wherein, one Planting compositions and include a kind of medicament, another compositions includes another medicament.The medicament of combination can be administered simultaneously or in a period of time Separately it is administered in section.Preferably, separately administration can produce preferable therapeutic effect.The compound of the present invention can pass through several minutes To several weeks be spaced in another medicament before and described another kind of reagent and/or be administered after described another kind of reagent simultaneously. Those skilled in the art generally can ensure that the time interval of delivery every time, and wherein, the medicament being separately administered remains able to described Cell, tissue or organism produce favourable combination effect.In one embodiment, those skilled in the art can take into account can Make cell, tissue or organism basic (the most less than about one minute) simultaneously contact two kinds of alternately material, three kinds, four kinds or More kinds of forms.In another embodiment, a kind of or more than one medicament can be administered in about 1 minute to 14 days.
On the other hand, the present invention provides the compound of the present invention or its physiologically acceptable salt or the medicine of the present invention Compositions is used for the application treating in the medicine of the disease of above-mentioned WNT path mediation in preparation.
On the other hand, the present invention provides a kind of compound or its salt preparing the present invention or the method for derivant.
In one embodiment, the compound of logical formula (I) can be according in the synthetic method described in following embodiment Any preparation.In described reaction, when expectation reactive functional groups (such as, hydroxyl, amino, imino group, thio group Or carboxyl) when being present in end product, these groups can be protected against them and unnecessarily participate in reaction.Conventional guarantor Protect group to use according to standard practice and (see for example T.W.Greene and P.G.M.Wuts, " the protection in organic chemistry Group " (Protecting Groups in Organic Chemistry), John Wiley and Sons, 1991).Described Synthetic method in use suitable leaving group include that halo leaving group and other routines known in the art are left away Group.Preferably, described leaving group is chlorine or bromine.
In another embodiment, the compound or its salt of the present invention can also hydrate form obtain, or they Crystal can include such as solvents used for crystallization (with solvate exist).Generally, salt can be by with the most alkaline Agent treated, preferably processes with alkali carbonate, alkali metal hydrogencarbonate or alkali metal hydroxide, more preferably uses Potassium carbonate or naoh treatment and change into the compound of free form.The compounds of this invention of addition salt forms can pass through Corresponding free acid is changed into the suitable acid treatment of all example hydrochloric acids etc.Noval chemical compound and salt thereof in view of free form Close relation between (including those salt that can be used as intermediate) form, such as at purification and the qualification process of noval chemical compound In, any content mentioning free cpds can be suitably interpreted as it is also mentioned that the salt of its correspondence.
Salt with the compound of the present invention of salt forming group can be prepared to use mode well known in the art.Therefore, logical The acid-addition salts of the compound of formula (I) can be by processing acquisition with acid or suitably anionite.The compound of the present invention Pharmaceutically acceptable salt can be by using organic acid or mineral acid by the compound of the logical formula (I) with basic nitrogen atom Be formed as acid-addition salts.
Preferably, suitable mineral acid includes but not limited to: halogen acids (such as hydrochloric acid), sulphuric acid or phosphoric acid.
Preferably, suitable organic acid includes but not limited to: carboxylic acid, phosphoric acid, sulfonic acid or sulfamic acid, such as acetic acid, third Acid, octanoic acid, capric acid, dodecylic acid, glycolic, lactic acid, fumaric acid, succinic acid, adipic acid, 1,5-pentanedicarboxylic acid., suberic acid, Azelaic Acid, Malic acid, tartaric acid, citric acid, aminoacid, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methyl Malaysia Acid, cyclohexane-carboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-ASA, phthalandione, phenylacetic acid, mandelic acid, Cortex Cinnamomi Acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2,1,5-naphthalene-two Sulfonic acid, 2-, 3-or 4-toluene sulfonic acide, methylsulfuric acid, ethyl sulfuric acid, lauryl sulphate acid, N-cyclohexylsulfamic, N-first Base-, N-ethyl-or N-propyl-amino sulfonic acid, or other organic proton acid, such as ascorbic acid.
Alternatively, in order to separate the purpose with purification, it is possible to use the most unacceptable salt, such as picrate Or perchlorate.But, in order to treat the purpose of use, when being applied in pharmaceutical dosage forms, only with pharmaceutically connecing The salt being subject to or free cpds.
In another embodiment, the compound of the present invention of non-oxidised form can be by suitable inert organic solvents In, at 0-80 DEG C, use reducing agent process, the N-oxide of the compound of the present invention prepare.Preferably, described reduction Agent is sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, Phosphorous chloride., phosphorus tribromide or the like.Preferably, Described inert organic solvents is acetonitrile, ethanol, aqueous dioxane or the like.
In another embodiment, the prodrug derivant of the compound of the present invention can be made by means commonly known in the art It is standby that (detailed description refers to Saulnier et al. (1994), biological organic and pharmaceutical chemistry bulletin (Bioorganic and Medicinal Chemistry Letters), volume 4, page 1985).In a preferred embodiment, suitable prodrug can By the compounds of this invention of non-derived and suitable carbamoylating agent (such as 1,1-acyloxyallcyl chlorine carbonic ester (1,1- Acyloxyalkylcarbanochloridate), p-nitrophenyl carbonate, or the like) reaction prepare.
In yet, the derivant of the compound of the protected present invention can pass through manner known in the art Preparation.Can " having at T.W.Greene to the detailed description being applicable to generate the technology of blocking group and removing blocking group Blocking group in chemical machine " in (third edition, John Wiley and Sons company limited, 1999) finds.
In another embodiment, the compound of the present invention can be prepared to the stereoisomer that it is independent.Prepared Journey includes: make the racemic mixture of compound react to generate a pair diastereomer chemical combination with optical activity resolving agent Thing, separates described diastereomer and reclaims optical voidness enantiomer.The fractionation of enantiomer can use the present invention's The derivant of the covalent diastereomeric of compound is carried out, or (such as crystallize is non-by using separable complex The salt of mapping) carry out.Diastereomer has different physical properties, shows that fusing point, boiling point, dissolubility, reaction are lived The aspects such as property, and diastereomer can be easy to by utilizing these differences to separate.Diastereomer can pass through Fractional crystallisation, chromatography or separated by separation based on different solubility/fractionation technology.The most optically pure mapping is different Structure body together with resolution reagent by be not result in racemic any put into practice method reclaim.It is applied to from racemic mixture The more detailed description of the technology splitting the stereoisomer of compound is disclosed in Jean Jacques, Andre Collet, Samuel H.Wilen, " enantiomer, racemate and isolation " (" Enantiomers, Racemates and Resolutions ") John Wiley and Sons company limited, 1981.
In sum, the compound of the present invention can be prepared by the method described in embodiment；And
Optionally, the compound of the present invention can be converted into pharmaceutically acceptable salt；
Optionally, the non-oxidised form of the compound of the present invention can be converted into pharmaceutically acceptable N-oxide；
Optionally, the independent isomer of the removable compound separating the present invention of isomer mixture；And
Optionally, the compounds of this invention of non-derived can be converted into pharmaceutically acceptable prodrug derivant.
In the case of the preparation process that initiation material is not particularly described, compound be known or can use with Prepared by method preparation or employing method as disclosed in Examples below that the known method of this area is similar.This area Those of skill will appreciate that above-mentioned transformation example only prepares the representative of the method for the compounds of this invention, and equally make By other well-known method.
Embodiment
By hereafter and describe the embodiment of preparation of the compounds of this invention in detail and be further illustrated by the present invention, but The present invention is not limited to this.
Abbreviation definition or lexical or textual analysis
DCM dichloromethane
DIEA N, N '-diisopropylethylamine
DMF N,N-dimethylformamide
Eq. equivalent
TEA triethylamine
THF oxolane
RT room temperature
EA ethyl acetate
Pd2(dba)3Three (dibenzalacetone) two palladium (0)
S-Phos 2-dicyclohexyl phosphino--2', 6'-dimethoxy-biphenyl
Pd(PPh3)4Tetrakis triphenylphosphine palladium
Embodiment 1:N-(4-(2-picoline-4-base) benzyl)-6-(2-picoline-4-base)-copyrine 2,7-1- Amine (compound 1)
Step 1:
2-cyanoacetamide (50g, 601.8mmol) and ethyl acetoacetate (75mL, 601.8mmol) are dissolved in MeOH In.KOH (37.0g, 1.1eq) is dissolved in MeOH, and dropwise adds to mixture, some white solids occur. In oil bath, described mixture is heated to reflux 8h, is then cooled to room temperature.Cross filter solid and be re-dissolved in hot water subsequently In, the most again filter.In filtrate, add 6N HCl neutralize until pH < 7.White solid again occurs and is filtered.Enter One step MeOH, water and MeOH wash described solid, then by vacuum drying, obtain end product 3-acetenyl-4-methyl Pyridine-2,6-glycol (productivity～41%)
Step 2:
3-acetenyl-4-picoline-2,6-glycol (28.0g, 195.2mmol) is dissolved in POCl3(60.0mL) in. Reactant mixture is sealed in manometer tube and is heated to 180 DEG C and continues 6h.After reaction is cooled to room temperature, remove under vacuo Remove the POCl of excess3.Lentamente trash ice is added to mixture, then solid occurs.Solid is filtered and does under vacuo Dry, obtain end product 2,6-bis-chloro-4-picoline-3-formonitrile HCN (productivity～92%), it is not necessary to be further purified.
Step 3
The aqueous isopropanol of the 2,6-bis-chloro-4-picoline-3-formonitrile HCN (20.0g, 107.5mmol) of 200mL adds Add DMF dimethylacetal (12.82g, 107.5mmol), and continue 18h 65 DEG C of stirring reactions.Instead After should being cooled to RT, precipitate it is collected by filtration and washs with 50mL isopropanol, air-drying, it is thus achieved that product 2, the chloro-4-of 6-bis- ((E)-2-(dimethylamino) vinyl) pyridine-3-formonitrile HCN (productivity～26%), it is not necessary to be further purified.
Step 4:
By chloro-for 2,6-bis-4-((E)-2-(dimethylamino) vinyl) pyridine-3-formonitrile HCN (4.0g, 16.6mmol) and The dense HCl of 20mL adds to sealing in pipe.18h is continued 45 DEG C of stirring reactions.After reaction is cooled to RT, frozen water is added to molten In liquid, form the slurry of buff.Precipitate it is collected by filtration and washs by cold water, ether and ethyl acetate, then existing It is dried under vacuum, it is thus achieved that flaxen solid 6,8-bis-chloro-2,7-naphthyridines-1 (2H)-one (productivity～80%).MS m/z 215.0(M+1)。1HNMR (300MHz, DMSO-d6): δ 11.75 (s, 1H), 7.76 (s, 1H), 7.50 (t, J=6.6Hz, 1H), 6.52 (d, J=6.6Hz, 1H).
Step 5:
Chloro-for 6,8-bis-copyrine 2,7-1 (2H)-one (3.0g, 13.96mmol) is dissolved in iPrOH (120mL) and is formed A kind of suspension.In ice bath, solution is cooled to 0 DEG C, the most dropwise adds hydrazine solution (5.6g, 80%, 10eq).? Mixture is stirred 15 minutes, then heated overnight in the oil bath of 55 DEG C under RT.After reactant mixture is cooled to RT, filter, Directly obtain solid, then wash described solid with 70mL MeOH and be dried under vacuum.Product 6-chloro-8-diazanyl-2,7-naphthalene Pyridine-1 (2H)-one (productivity～98%) is directly used in next step reaction, it is not necessary to be further purified.
Step 6:
Chloro-for 6-8-diazanyl-copyrine 2,7-1 (2H)-one (1.50g, 7.12mmol) is dissolved in MeCN (90mL) with life Become a kind of suspension.Add 1N NaOH (17.80mL, 2.5eq), then the water (107.80mL) of equivalent is added to mixture In.Heat at 50 DEG C and stir reactant mixture until described mixture becomes the solution of clarification.By the coldest for described solution But to 0 DEG C, and dropwise add NaOCl (11.05g, 12% solution, 2.5eq), be then stirred at room temperature reaction overnight. After completion of the reaction, described solution is cooled to 0 DEG C, is subsequently adding 1N HCl and neutralizes (pH～6).Collect precipitate and use 100mL x 2EA extracts filtrate.Organic layer is merged and passes through Na2SO4It is dried, evaporation, it is thus achieved that extra crude product.Merge Solid matter 6-chloro-2,7-naphthyridines-1 (2H)-one (productivity～93%) for next react in, it is not necessary to be further purified.MS m/z 181.1(M+1)。
Step 7:
Chloro-for 6-copyrine 2,7-1 (2H)-one (400mg, 2.2mmol) is added to POCl by manometer tube3(20.0mL) In.Reactant mixture is heated to 160 DEG C and continues 4h, obtain the solution of clarification.Described solution is cooled to room temperature and pours DCM into In, add trash ice the most lentamente.By saturated NaHCO3Add to mixture to neutralize the HCl produced in reaction.Very Remove DCM under empty and extract remaining aqueous solution with 100mL x 2EA.The organic layer of merging is washed once, then with saline Use Na2SO4Being dried, then vaporising under vacuum, it is thus achieved that solid 1,6-bis-chloro-2,7-naphthyridines (productivity～73%) is used for next step Rapid reaction, it is not necessary to be further purified.MS m/z 199.0(M+1).
Step 8:
By (4-bromophenyl) methylamine (1.00g, 5.37mmol) and 2-picoline-4-base-4-boric acid (883.30mg, 6.45mmol) it is dissolved in BuOH (10.0mL) and water (2.0mL).At N2Lower interpolation K3PO4(2.28g,10.75mmol),Pd2 (dba)3(120.20mg, 0.27mmol) and S-phos (220.70mg, 0.54mmol).Reactant mixture is sealed in manometer tube In and be heated to 125 DEG C continue 1h.After reaction is cooled to RT, described mixture is poured into water and uses 100mL x 3EA extracts.The organic layer merged with saline washing, Na2SO4It is dried and is concentrated under vacuum, it is thus achieved that crude product.Pass through silicagel column (comprise～2N NH with containing 10%MeOH3) DCM pure solid, it is thus achieved that pure (4-(2-picoline-4-base) phenyl) methylamine (productivity～89%).MS m/z 199.1(M+1).
Step 9:
By chloro-for 1,6-bis-copyrine 2,7 (160mg, 0.80mmol) and (4-(2-picoline-4-base) phenyl) methylamine (239.10mg, 1.21mmol) is dissolved in BuOH (5.0mL), is then heated to 115 DEG C overnight.After reaction is cooled to RT, Remove organic solvent under vacuo.By flashchromatography on silica gel EA/ hexane (1:1) purification of crude product, it is thus achieved that solid N-(4- (2-picoline-4-base) benzyl)-6-chloro-copyrine 2,7-1-amine (productivity～90%).MS m/z 361.1(M+1).
Step 10:
By N-(4-(2-picoline-4-base) benzyl)-6-chloro-copyrine 2,7-1-amine (50.00mg, 0.14mmol) It is dissolved in BuOH (3.0mL) and water (0.6mL) with 2-picoline-4-base-4-boric acid (56.90mg, 0.42mmol).At N2 Lower by K3PO4(88.20mg,0.028mmol)、Pd2(dba)3(6.20mg, 0.014mmol) and S-phos (11.40mg, 0.011mmol) add to mixture.Reactant mixture is sealed in manometer tube, is then heated to 105 DEG C overnight.Instead After should being cooled to RT, described mixture is poured into water and extracts three times with EA.The organic layer merged with saline washing, uses Na2SO4It is dried and is concentrated under vacuum.It is further purified crude product by the pre--TLC method DCM containing 5%MeOH, thus obtains Obtain end product N-(4-(2-picoline-4-base) benzyl)-6-(2-picoline-4-base)-copyrine 2,7-1-amine (to produce Rate～70%).MS m/z 418.2(M+1).1HNMR(300MHz,CDCl3):δ2.46(s,3H),2.63(s,3H),4.94(d, J=5.10Hz, 2H), 5.94 (br, 1H), 6.97 (d, J=5.70Hz, 1H), 7.31 (d, J=4.20Hz, 1H), 7.36 (s, 1H), 7.54 (d, J=8.10Hz, 2H), 7.63 (d, J=8.40Hz, 2H), 7.90 (s, 1H), 8.19 (d, J=6.00Hz, 1H),8.22(s,1H),8.51(m,2H),9.08(s,1H),9.30(s,1H)。
Embodiment 2:N-(3-methyl-4-(2-picoline-4-base) benzyl)-6-(2-picoline-4-base)-2,7- Naphthyridines-1-amine (compound 2)
Step 1:
By chloro-for 6-copyrine 2,7-1 (2H)-one (200mg, 1.10mmol) and 2-picoline-4-base-4-boric acid (227.60mg, 1.66mmol) is dissolved in BuOH (5.0mL) and water (1.0mL).At N2Lower addition K3PO4(705.20g, 3.32mmol)、Pd2(dba)3(49.60mg, 0.22mmol) and S-phos (91.00mg, 0.11mmol).Anti-by manometer tube Answer mixture to be heated to 130 DEG C and continue 1h.After reaction is cooled to RT, pour the mixture in water, extract three times with EA.Use salt The organic layer that water washing merges, passes through Na2SO4It is dried, is concentrated under vacuum, it is thus achieved that crude product.By column chromatography with containing 5% Crude product described in the DCM purification of MeOH is to obtain finalization compound 6-(2-picoline-4-base)-copyrine 2,7-1 (2H)-one (productivity～61%).MS m/z 238.1(M+1).
Step 2:
6-(2-picoline-4-base)-copyrine 2,7-1 (2H)-one (150mg, 0.63mmol) is dissolved in POCl3 (15.0mL) in, seal pressure pipe and be heated to 160 DEG C continue 4h.After reaction is cooled to RT, remove excess under vacuo POCl3.Trash ice is added in mixture lentamente, then adds NaHCO3Neutralize until pH～7.5.Solution three is extracted with EA Organic layer that is secondary, that merge with saline washing, Na2SO4It is dried, is concentrated under vacuum.By column chromatography EA/ hexane (1:1) purification Crude product, it is thus achieved that the chloro-6-of compound 1-(2-picoline-4-base)-2,7-naphthyridines (productivity～55%).MS m/z 256.1(M +1)。
Step 3:
By chloro-for 1-6-(2-picoline-4-base)-copyrine 2,7 (10.00mg, 0.039mmol) and (3-methyl-4-(2- Picoline-4-base) phenyl) methylamine (10.00mg, 0.047mmol) is dissolved in toluene (1.0mL).At N2Lower by KOtBu (8.80mg,0.078mmol)、Pd(OAc)2(0.90mg, 0.0039mmol) and BINAP (4.90mg, 0.0078mmol) add To mixture.Reaction is heated to 100 DEG C overnight.After described reaction is cooled to RT, pours the mixture in water, extract with EA Take three times.The organic layer merged with saline washing, Na2SO4It is dried, is then concentrated under vacuum.By pre--TLC EA/ hexane (4:1) purification of crude product is to obtain N-(3-methyl-4-(2-picoline-4-base) benzyl)-6-(2-picoline-4- Base)-copyrine 2,7-1-amine (8.8mg, productivity～52%).1H NMR(300MHz,CDCl3):δ2.31(s,3H),2.63(s, 3H), 2.70 (s, 3H), 4.91 (d, J=5.10Hz, 2H), 5.88 (br, 1H), 7.00 (d, J=5.40Hz, 1H), 7.08 (d, J =5.10Hz, 1H), 7.12 (s, 1H), 7.22 (d, J=7.50Hz, 1H), 7.36 (m, 2H), 7.77 (d, J=4.50Hz, 1H), 7.88 (s, 1H), 7.98 (s, 1H), 8.24 (d, J=6.00Hz, 1H), 8.53 (d, J=4.80Hz, 1H), 8.64 (d, J= 5.40Hz,1H),9.31(s,1H)。MS m/z432.2(M+1)。
Embodiment 3:6-(3-fluorophenyl)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) isoquinolin-1- Amine (compound 3)
Step 1:
6-bromo-isoquinoline (1.80g, 8.66mmol) is dissolved in DCM (40mL), after reaction is cooled to 0 DEG C, a small amount of, Add m-CPBA (2.30g, 1.3eq, most 77%) lentamente.Reaction is warming up to RT to generate a kind of white suspension.4 In individual hour, 100mLDCM is added to solution, then uses saturated Na2CO3Solution, water and saline washing.Use Na2SO4It is dried Separate organic layer and remove solvent under vacuo, it is thus achieved that be not required to the yellow solid N-oxide 6-bromo-isoquinoline being further purified (1.82g, productivity～93%).
Step 2:
N-oxide 6-bromo-isoquinoline (1.82g, 8.12mmol) is dissolved in dry DCM (80mL), under RT by Drip and add POCl3(1.12ml,1.5eq).Reaction is heated to 45 DEG C and continues 2 hours.After reaction is cooled to RT, under vacuo Remove DCM and the POCl of excess3.Crude product is re-dissolved in 100mL DCM, and uses saturated Na2CO3, water and salt washing Wash.Na2SO4It is dried the organic layer separated, is then concentrated to give brown solid.By the rapid column chromatography DCM containing 2%MeOH Purification of crude product is to obtain faint yellow solid 6-bromo-1-chlorine isoquinolin (1.27g, productivity～65%).MS m/z 242.0(M+ 1)。
Step 3:
In manometer tube, by (6-chloropyridine-3-base) methylamine (300mg, 2.1mmol) and 2-picoline-4-ylboronic acid (345mg, 2.52mmol) is dissolved in n-butyl alcohol (10mL) and water (2mL).Add K under nitrogen protection3PO4(893mg, 4.2mmol)、Pd2(dba)3(96.3mg, 0.105mmol) and S-phos (86.4mg, 0.21mmol).Reaction is heated to 125 DEG C continue 30 minutes, be then cooled to room temperature.Solution is poured into water and extracts three times with EA.The organic of merging is washed with saline Layer, and use Na2SO4It is dried, is then concentrated under vacuum.(contained～2N NH with containing 10%MeOH by flash chromatography3) DCM be further purified crude product with obtain pure (6-(2-picoline-4-base) pyridin-3-yl) methylamine (0.19g, productivity～ 45%).MS m/z 200.1(M+1).
Step 4:
By bromo-for 6-1-chlorine isoquinolin (100mg, 0.41mmol) and (6-(2-picoline-4-base) pyrrole in sealing pipe Pyridine-3-base) methylamine (165mg, 0.82mmol) is dissolved in 0.5mL n-butyl alcohol.Reaction is heated to 160 DEG C and continues 6h, then It is cooled to RT.(contained～2N NH with containing 8%MeOH by flash chromatography3) DCM purification of crude product bromo-to obtain pure 6- N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) isoquinolin-1-amine (116mg ,～70%).MS m/z 405.2 (M+1)。
Step 5:
By bromo-for 6-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) isoquinolin-1-amine (20mg, 0.05mmol), 3-flurophenyl boronic acid (10.5mg, 0.075mmol), Na2CO3(21mg, 0.2mmol) and tetrakis triphenylphosphine palladium (5.8mg, 0.005mmol) adds to manometer tube.Dioxane/water (3:1,2mL) is added to pipe, and is heated to 125 DEG C continue 10 minutes.After reaction is cooled to RT, extract 3 times with 50mL water dilute solution and with EA.Use Na2SO4It is dried merging Organic layer, and be concentrated under vacuum.(contained～2N NH with containing 10%MeOH by flash chromatography3) DCM be further purified Crude product is to obtain pure 6-(3-fluorophenyl)-N-((6-(2-picoline-4-base) pyridin-3-yl) methyl) isoquinolin-1- Amine (15.8mg ,～75%).1H NMR (400MHz, CDCl3): δ 2.71 (s, 3H), 5.00 (d, J=5.6Hz, 2H), 7.32- 7.38 (m, 2H), 7.59-7.65 (m, 1H), 7.75-7.83 (m, 3H), 8.10 (d, J=8.4Hz, 1H), 8.21 (d, J= 8.8Hz, 1H), 8.27-8.31 (m, 2H), 8.39 (s, 2H), 8.72 (d, J=8.8Hz, 1H), 8.79 (d, J=6.0Hz, 1H), 8.91 (d, J=1.6Hz, 1H), 10.02 (s, 1H).MSm/z 421.2(M+1).
Embodiment 4:N-(4-(2-picoline-4-base) benzyl)-2-(2-picoline-4-base)-1,6-naphthyridines-5- Amine (compound 4)
Step 1:
1,6-naphthyridines-5 (6H)-one (2.9g, 19.84mmol) is dissolved in POCl3(40mL), in, it is then heated to 100 DEG C continue 24h.After reaction is cooled to room temperature, remove the POCl of excess under vacuo3.It is slowly added into a small amount of trash ice Saturated Na2CO3Solution, and produce a large amount of bubble and solid.Cross filter solid, then will extract solution 3 times with EA.Use Na2SO4 It is dried the organic layer merged, and is concentrated under vacuum.The solid that merging is further dried under vacuo is not required to further to obtain The 5-chloro-1,6-naphthyridines (2.6g, productivity～80%) of purification.MS m/z 165.1(M+1).
Step 2:
By chloro-for 5-1,6-naphthyridines (1.5g, 9.11mmol) is dissolved in DCM (45mL), is then cooled down by ice bath, few Measure, add m-CPBA (3.7g, 2eq, most 77%) lentamente.Reaction is warming up to RT and keeps 3 hours.Again by 100mL's DCM adds to solution, then uses saturated Na2CO3Solution, water and saline washing.Na2SO4It is dried organic layer, and in vacuum Lower concentration is to obtain the yellow solid N-oxide 5-chloro-1 being not required to be further purified, 6-naphthyridines (1.25g, productivity～76%).
Step 3:
N-oxide 5-chloro-1,6-naphthyridines (1.2g, 6.64mmol) is dissolved in dry DCM (30mL), adds Et3N (1.85mL, 13.29mmol), the most dropwise adds and is dissolved in the POCl in the DCM that 5mL is dried3(0.93mL, 9.97mmol).Reaction is heated to 48 DEG C and continues 2h.In solution, add the DCM of 100mL again, and use saturated Na2CO3Molten Liquid, water and saline washing.Na2SO4It is dried organic layer, and is concentrated under vacuum to obtain yellow solid.Used by silicon column chromatography EA/ hexane (1:4) is further purified crude product to obtain white solid 2,5-bis-chloro-1,6-naphthyridines (0.6g, productivity～45%). MS m/z199.0(M+1)。
Step 4:
By chloro-for 2,5-bis-1,6-naphthyridines (200mg, 1.0mmol), 2-picoline-4-base-4-boric acid (137mg, 1.0mmol),Na2CO3(424mg, 4.0mmol) and tetrakis triphenylphosphine palladium (116mg, 0.1mmol) add in flask, add 16mL dioxane and 4mL water.Reaction is sufficiently stirred for and is heated to 90 DEG C and continues 4h.After reaction is cooled to RT, use 100mL Water dilute solution also extracts 3 times with EA.Na2SO4It is dried the organic layer merged, and is concentrated under vacuum.Pass through flash chromatography It is further purified crude product to obtain the chloro-2-of solid 5-(2-picoline-4-base)-1,6-naphthyridines with EA/ hexane (1:1) (143mg, productivity～56%).MS m/z 256.1(M+1).
Step 5:
By chloro-for 5-2-(2-picoline-4-base)-1,6-naphthyridines (20.00mg, 0.078mmol) and (4-(2-methyl pyrrole Pyridine-4-base) phenyl) methylamine (25mg, 0.118mmol) is dissolved in toluene (2.0mL).At N2Lower by KOtBu(13.2mg, 0.118mmol)、Pd(OAc)2(2.7mg, 0.012mmol) and BINAP (15.0mg, 0.024mmol) add to mixture. Reaction is heated to 100 DEG C overnight.After reaction is cooled to RT, described mixture is poured into water, extracts three times with EA.Use salt The organic layer that water washing merges, Na2SO4It is dried, is then concentrated under vacuum.Purified by the pre--TLC DCM containing 8% methanol Crude product is to obtain N-(4-(2-picoline-4-base) benzyl)-2-(2-picoline-4-base)-1,6-naphthyridines-5-amine (31mg, productivity～61%).1H NMR (400MHz, DMSO-d6): δ 9.12 (d, J=8.8Hz, 1H), 8.77-8.83 (m, 2H), 8.49 (d, J=8.4Hz, 1H), 8.40 (s, 1H), 8.31 (d, J=6.4Hz, 1H), 8.21 (s, 1H), 8.11 (d, J= 5.6Hz, 1H), 8.06 (d, J=6.4Hz, 1H), 7.99 (d, J=8.4Hz, 2H), 7.65 (d, J=8.4Hz, 2H), 7.23 (d, J=6.4Hz, 1H), 5.76 (s, 1H), 4.93 (d, J=5.6Hz, 2H), 2.72 (s, 6H).MS m/z 432.2(M+1).
Embodiment 5:N-(4-(2-picoline-4-base) benzyl)-2-phenylpyridine also [4,3-b] pyrazine-5-amine (is changed Compound 5)
Step 1:
By phenyl Biformyl monohydrate (940mg, 6.99mmol) and 2-chloro-3,4-diamino-pyridine (1000mg, 6.99mmol) add in 20mL ethanol.Mixture is made to reflux overnight.After reaction cooling, thick precipitated product is filtered and uses 15mL washing with alcohol, is then dried under vacuum, it is thus achieved that be not required to 5-chloro-2-phenylpyridine also [3, the 4-b] pyrrole being further purified Piperazine (1.28g, productivity～76%), MS m/z 241.0 (M+1)；1H NMR(300MHz,DMSO-d6):δ9.82(s,1H), 8.64 (d, J=6.0Hz, 1H), 8.38-8.43 (m, 2H), 8.07 (d, J=6.0Hz, 1H), 7.64-7.68 (m, 3H).
Step 2:
By N-(4-(2-picoline-4-base) benzyl)-2-phenylpyridine also [3,4-b] pyrazine-5-amine (50mg, 0.21mmol) it is dissolved in toluene (4.0mL) with (4-(2-picoline-4-base) phenyl) methylamine (42mg, 0.21mmol).? N2Lower by KOtBu(24mg,0.21mmol)、Pd(OAc)2(4.5mg, 0.021mmol) and BINAP (26.4mg, 0.042mmol) Add to mixture.Reaction is heated to 100 DEG C overnight.After reaction is cooled to room temperature, pours the mixture in water, use EA Extract 3 times.The organic layer merged with saline washing, Na2SO4It is dried, is then concentrated under vacuum.By flash chromatography with containing The DCM purification of crude product of 7%MeOH, it is thus achieved that N-(4-(2-picoline-4-base) benzyl)-2-phenylpyridine also [4,3-b] Pyrazine-5-amine (61mg, productivity～72%).MS m/z=404.2 (M+1)；1H NMR(400MHz,DMSO-d6)δ9.53(s, 1H), 8.77 (d, J=6.4Hz, 1H), 8.35-8.39 (m, 2H), 8.21 (s, 1H), 8.11 (d, J=6.0Hz, 1H), 8.07 (d, J=6.4Hz, 1H), 7.96 (d, J=8.4Hz, 2H), 7.60-7.65 (m, 5H), 7.14 (d, J=6.0Hz, 1H), 5.76 (s, 1H), 4.90 (d, J=6.4Hz, 2H), 2.71 (s, 3H).
Those skilled in the art are it should be clearly understood that can be by the scheme identical with embodiment 1-5 with knowing other compounds Preparation.
Compound list:
Experimental example 6:WNT path reporter gene assays
Material and method:
Plasmid transfected fibroblast NIH3T3 with the luciferase gene comprised by 5 copy TCF element drives (American type culture collection, Manassas, Virginia).By 1 μ g/mL bleomycin (Gibco/ Invitrogen, Carlsbad, Canada) the stable cell that obtains of screening 37 DEG C, in atmosphere containing 5%CO2Bar Under part, it is being supplemented with 10%FBS (Invitrogen), 50 units/mL penicillin, 50 μ's g/mL streptomycin (Invitrogen) The Eagle's culture medium (DMEM, Invitrogen, Carlsbad, Canada) of Dulbecco's improvement is cultivated.With containing by The HEK293 cell (ATCC) of the plasmid Transfection ofsuspension of the total length WNT-3a cDNA sequence of the people that CMV promoter drives.Supplementing Screening in the FreeStyle 293 culture medium (Invitrogen) of 100ug/mL G418 is had to stablize cell.
NIH3T3TCF-Luc cell and 293WNT3a cell are in 96 holes with the DMEM culture medium supplementing 0.5%FBS Co-cultivation in plate.After 16 hours, at Steady-GloTMDetection Lampyridea fluorescence in Luciferase Assay System (Promega) The activity of element enzyme.During co-cultivation, with the compound treated cells of the present invention of variable concentrations.IC50 is defined as making Luminous intensity reduces the compound concentration of 50%.For quantity and the activity of standardized cell, it is repeated twice CellTiter subsequently Glo detects.
In WNT signal path reporter gene assays, the IC of all compounds in the present invention50Value both less than 5 micromoles (IC50＜ 5 μMs).Selected examples of compounds is listed in the table below:
The study mechanism of experimental example 7:WNT pathway inhibitor
To in preliminary analysis, suppression is by the chemical combination of the TCF reporter gene activity of the Wnt-3a cell induction of co-cultivation Thing has carried out study mechanism subsequently to determine the application point of compound.Have rated two different activators, one is passed through purification Wnt-3a recombiant protein (StemRD Inc., Burlingame, CA) be evaluated, another is by the inhibitor of GSK-3b 6-bromo-isatin-3'-oxime (StemRD Inc., Burlingame, CA) is evaluated.
Some reactive compounds of the result display present invention of this study mechanism interact with receptor at WNT-3a The activation of some suppression WNT path before, without suppression restructuring WNT-3a protein activation TCF reporter gene.This effect Material standed for includes but not limited to: wntless/evenness interrupted (Wls/Evi), porcupine (Porcn), Vps35p。
The effect to cancerous cell of the experimental example 5:WNT pathway inhibitor
The compound of suppression Wnt secretion and Cellular Signaling Transduction Mediated is expected to suppression and depends on the conduction of autocrine Wnt signal The propagation of cancerous cell.Wnt pathway inhibitor needs Wnt to known to the effect grappling of the cell proliferation in 2-D culture medium Independent growths in the cell line of autocrine signal conduction and anti-apoptotic.By to the works delivered at present mentions Compound is evaluated in the standard analysis of Wnt dependent cell system, and these Wnt dependent cell system includes: PA-1 (ovary monster Cancer), MDA-MB-157 (breast carcinoma), Saos-2 (osteosarcoma), SNU1076 (head and neck squamous cell carcinoma).In these cell lines The effect of the inhibitor observed further confirms that the activity of these desired compounds.
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Claims (15)

1., as compound or its physiologically acceptable salt of WNT signal transduction inhibitor, described compound has The structure of following formula I:
Wherein,
By X5,X6,X7And X8The core texture of the formula I of definition is selected from:
Y1、Y2And Y3Independently be hydrogen；
By X1、X2、X3And X4Ring in the formula I of definition is selected from:
R1Independently selected from: hydrogen, halogen, C1-6Alkyl, quinolyl,C6-30Aryl, containing 1-2 selected from N, O and The heteroatomic 3-6 unit Heterocyclylalkyl of S and containing 1-4 the heteroatomic 5 or 6 yuan of heteroaryls selected from N, O and S；Wherein, quinoline Base,C6-30Each in aryl, 3-6 unit Heterocyclylalkyl, 5 or 6 yuan of heteroaryls can be identical or not by 1 or 2 Same R4Optionally replace；Described 5 or 6 yuan of heteroaryls are selected from:
R2Independently selected from: hydrogen, halogen, C1-6Alkyl, quinolyl,C6-30Aryl, containing 1-4 selected from N, O and Heteroatomic 5 or 6 yuan of heteroaryls of S；Wherein, quinolyl,C6-30Each in aryl, 5 or 6 yuan of heteroaryls Individual can be by 1 or 2 identical or different R4Optionally replace；Described 5 or 6 yuan of heteroaryls are selected from:
R4Separately it is selected from: hydrogen, halogen, cyano group, C1-6Alkoxyl ,-C (O) OR5、-C(O)R5、C1-6Alkyl, wherein, C1-6 Alkoxyl ,-C (O) OR5、-C(O)R5、C1-6Each in alkyl can be by halogen, amino, hydroxyl, C1-6Alkoxyl or cyano group Optionally replace；
R5Independently selected from: hydrogen and C1-6Alkyl.
2. compound as claimed in claim 1, wherein, R1Independently selected from: hydrogen, fluorine, chlorine, methyl,Phenyl, Morpholinyl, piperazinyl and containing 1-4 selected from heteroatomic 5 or 6 yuan of heteroaryls of N and S；And described 5 or 6 yuan of heteroaryls choosing From:
R2Independently selected from: hydrogen, fluorine, chlorine, methyl,Phenyl, morpholinyl and piperazinyl and containing 1-4 N and O Heteroatomic 6 yuan of heteroaryls, and described 6 yuan of heteroaryls are selected from:
R4Separately it is selected from: hydrogen, fluorine, chlorine, cyano group ,-CH3、-CHF2、-CF3、-OCH3、-COOCH3。
3. a pharmaceutical composition, it comprises the compound described in the claims 1 or 2 or it is physiologically acceptable Salt.
4. pharmaceutical composition as claimed in claim 3, it is Orally administered composition, Injectable composition or suppository.
5. pharmaceutical composition as claimed in claim 4, wherein, described Orally administered composition is tablet or gelatine capsule；Described can Injectable composition is aqueous isotonic solutions or suspension；Described suppository is prepared from by fats emulsion or suspension.
6. pharmaceutical composition as claimed in claim 3, it also comprises diluent, lubricant, binding agent, disintegrating agent and additive In at least one,
Described diluent is selected from: lactose, glucose, sucrose, mannitol, sorbitol, cellulose and glycine；
Described lubricant is selected from: silicon dioxide, Talcum, stearic acid, stearic magnesium salt and calcium salt and Polyethylene Glycol；
Described binding agent is selected from: magnesium silicate aluminium salt, gelatinized corn starch, gelatin, tragamayth, methylcellulose, carboxymethyl cellulose Sodium and polyvinylpyrrolidone；
Described disintegrating agent is selected from: starch, agar, alginic acid and sodium salt thereof and effervescent mixture；
Described additive is selected from: absorbent, coloring agent, flavoring agent and sweetener.
7. pharmaceutical composition as claimed in claim 3, it contains at least one adjuvant further, and described adjuvant is selected from: anticorrosion Agent, stabilizer, wetting agent, emulsifying agent, solution promoters, for regulating salt and the buffer agent of osmotic pressure.
8. pharmaceutical composition as claimed in claim 7, it comprises solubilizing agent, stabilizer, tension-elevating agent, buffer agent further And preservative.
9. pharmaceutical composition as claimed in claim 8, wherein, described pharmaceutical composition local application and be aqueous solution, The form of ointment, cream or gel.
10. any one of compound described in claim 1 or 2 or its physiologically acceptable salt and claim 3 to 9 Described pharmaceutical composition secretes the application in the medicine of WNT in preparation for suppression from cell.
Any one of compound described in 11. claim 1 or 2 or its physiologically acceptable salt and claim 3 to 9 Described pharmaceutical composition is used for suppressing the application in the medicine of WNT signal conduction in cell in preparation.
Any one of compound described in 12. claim 1 or 2 or its physiologically acceptable salt and claim 3 to 9 Described pharmaceutical composition is used for the application treating in the medicine of the disease of WNT path mediation in preparation.
13. apply as claimed in claim 12, and wherein, described disease is cancer, fibrosis, osteoarthritis, parkinson disease, regards Nethike embrane is sick, degeneration of macula.
14. apply as claimed in claim 13, and wherein, described cancer is selected from: include small cell lung cancer and nonsmall-cell lung cancer Pulmonary carcinoma, breast carcinoma, carcinoma of prostate, carcinoid, bladder cancer, gastric cancer, cancer of pancreas, hepatocarcinoma or hepatocarcinoma, hepatoblastoma, knot straight Intestinal cancer, renal carcinoma and head and neck squamous cell cancer, esophageal carcinoma, ovarian cancer, cervical cancer, carcinoma of endometrium, mesothelioma, melanin Tumor, sarcoma, osteosarcoma, liposarcoma, thyroid carcinoma, fibroma durum, acute myeloblastic leukemia (AML), chronic granulocyte are white Disorders of blood (CML).
15. apply as claimed in claim 13, and wherein, described fibrosis is selected from: systemic sclerosis, fibrosis of skin, spy The property sent out pulmonary fibrosis, renal fibrosis, hepatic fibrosis, drug-induced fibrosis and radioactive fibrosis.
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